Introduction to Natural Products

Chemistry

Natural Product
- is commonly reserved for those
organic compounds of natural origin that
are unique to one organism, or common
to a small number of closely related
organisms
 Cells of organisms - plants, fungi,
bacteria, lichens, insects, animals
- produce a large variety of organic
compounds.
 Many substances were obtained
anciently, e.g. foodstuffs, building
materials, dyes, medicinals, and other
extracts from nature.
Examples :
 MORPHINE
- in two species of poppy: Papaver
somniferum and P. setigerum
 PENICILLINS
- are produced by a few species of
fungi, Penicillium
Recipes from Medieval Times :

Ambroise Pare (1517-90)

- treated gunshot wounds with a concoction of
chamomile, mililot flowers, lavender, rosemary,
sage, thyme and red roses boiled in white wine

Thomas Sydenham (1624-89)

- prescribed Peruvian bark (cinchona tree)
mixed with syrup of cloves for malaria
Natural Products

 Crude aqueous extracts of

certain plants and animals
provided pigments, such as :

indigo (blue pigment from woad Indigo

plant)

alizarin (red pigment dye from

madder roots)

Alizarin
Indigo Alizarin
 As Medicines:

• Ephedrine - a sympathomimetic
amine (for respiratory ailments)
isolated from Ephedra sinica

• Ricinine - a purgative from seeds

of Castor oil plant (Ricinus
cummunalis)

• Salicin - an anti-inflammatory
agent produced from willow bark;
closely related to the chemical
make-up of aspirin
 
As Poison
 Strychnine (poison)
- was the first alkaloid to be
identified in plants of Strychnos
Loganiaceae. Strychnos was
named by Carl Linnaeus in 1753.
- was first discovered by French
chemists
Joseph Bienaimé Caventou and
Pierre-Joseph Pelletier in 1818
- poison for rodents and small
predators
As Poison
 Nicotine
- an alkaloid found in the nightshade
family of plants (Solanaceae) that acts
as a nicotinic acetylcholine agonist and
a monoamine oxidase inhibitor
- is named after the tobacco plant
Nicotiana tabacum
- Nicotine was first isolated from the
tobacco plant in 1828 by physician
Wilhelm Heinrich Posselt and chemist
Karl Ludwig Reimann of Germany, who
considered it a poison
Narcotics and Hallucinogens :

 Morphine (narcotic analgesic)

- the most abundant alkaloid found
in opium, the dried sap (latex)
derived from shallowly slicing the
unripe seedpods of the
Papaver somniferum poppy.
- it was first isolated in 1804 by
Friedrich Sertürner, first distributed
by him in 1817, and first
commercially sold by Merck in 1827
 Cocaine
(benzoylmethylecgonine)
- narcotic stimulant
- is a crystalline tropane
alkaloid that is obtained from the
leaves of the coca plant (family
Erythroxylaceae)
The cocaine alkaloid was first
isolated by the German chemist
Friedrich Gaedcke in 1855.
Gaedcke named the alkaloid
"erythroxyline"
• Tetrahydrocannabinol 
- principal psychoactive
constituent of the cannabis plant
(marijuana, hashish),
Cannabis indica

 
 Stimulant

• Caffeine
- is a bitter, white crystalline
xanthine alkaloid that acts as a
stimulant drug.

Common sources of caffeine are

coffee, tea, soft drinks and energy
drinks, and (to a lesser extent)
chocolate derived from cocoa beans

 
 Perfumes:

• Linalol, found in plants, mainly

from the families Lamiaceae
(mints, scented herbs),
Lauraceae (laurels, cinnamon,
rosewood), and Rutaceae (citrus
fruits)

• Geraniol, a monoterpenoid
and an alcohol in rose oil which
is used as a mosquito repellent
 
 Spices

• Cinnamaldehyde (cinnamon)
This pale yellow, viscous liquid
occurs naturally in the bark of
cinnamon trees and other species
of the genus Cinnamomum, is
used as flavoring agent

• Diallyl disulfide (garlic) an

organosulfur compound derived
from garlic and a few other genus
Allium plants. It is a yellowish
liquid which is insoluble in water
and has a strong garlic odor
 
Introduction to Natural Products
Chemistry
 Mild heating of certain plants afforded perfumed
distillates.

 Plants and animals have provided substances

used for their biological activity, to heal or to kill,
and form the foundation for folk medicine. 
Most natural products have usually come
from plants and microorganisms due to practical
difficulties in extracting them from animals.
Introduction to Natural Products
Chemistry
 Plants are particularly interesting because:
- They have the broadest spectrum of
biosynthetic capability, and produce a wide
variety of compounds.
- They use simple starting materials:  water,
carbon dioxide, nitrogen (elemental and in
salts), phosphorus compounds, and salts.
- Their biosynthetic paths are known
Introduction to Natural Products
Chemistry
 In the late 1700's, chemists moved from
myth and mystery to basics of modern
scientific methods to begin to uncover
the true properties of natural extracts
from biological systems.
 They discovered that natural extracts
had more complex compositions and
properties than salts and minerals.
 1769-85 Scheele showed tartaric acid in grapes,
citric acid in lemons, malic acid in apples, gallic acid
in galls, lactic acid in milk, uric acid in urine.

 1772-7 Lavoisier burned sugar, ethanol and acetic

acid in oxygen and found only CO2 and H2O. Later
studies by others found that some natural substances
when burned also gave off nitrogen hence must also
contain nitrogen.
Introduction to Natural Products
Chemistry
 This lead Berzelius, in 1807, to distinguish
between "inorganic" and "organic”
"Organic" substances were believed to be
obtainable only from organs of living systems and
could not be man-made because only living
systems have the vital ("life") force. 
"Inorganic" materials were from non living, e.g.
mineral sources.)

 In the 1800's, organic chemistry was exclusively

the study of natural products.
 1828 Wöhler showed that he could make urea, hence,
the “vital force” of living organisms was not needed to
make organic chemicals.

 1833 Persoz and Payen first noted enzyme activity.

The concept of vitalism now transferred to enzymes in
whole cells.

 1897 Büchner showed enzyme activity in cell-free

solutions, so vitalism suffered a final blow.
 19th C. The blossoming of the study of organic
molecules gradually split into the study of man-made
organic chemicals (the organic chemicals and Organic
Chemistry of today) and organic chemicals made by
organisms (Natural Products and Natural Product
Chemistry of today). “Physiological Chemistry” is
the study of enzymes and the chemistry in
organisms.
 1891 Kössel, a German Physiological Chemist,
proposed that the metabolism of organisms could be
divided into two types. Primary metabolism was the
basic biochemistry common to all cells. Secondary
metabolism was the type of biochemistry found only in
some species.

Thus to physiological chemists, later to be called

biochemists, Secondary Metabolites are what chemists
call Natural Products.
 20th C. Physiological Chemistry split off from
Chemistry Departments and became
Biochemistry ... but that split normally left Natural
Products being studied in Chemistry Departments
and now ignored by biochemists. None of the major
introductory biochemistry texts in the library give
the term Natural Product in their indices!
 Are synthetic chemicals different
from natural ones?
 Synthetic chemicals are made by the use of chemically
reactive reagents. The chemicals tend to bring about
changes to structures – addition, subtraction,
substitution and rearrangements.

 Natural Products are made by enzymes which can be

much more selective – they can target their action on
parts of the molecule by bringing the active site of the
enzyme into close proximity with one part of the
molecule to be changed
 Natural Products
 Secondary metabolites of complex structure,
of restricted distribution or characteristic of
specific sources (genera and species of plants
and microorganisms) than are the primary
metabolites

 Biosynthesized from -amino acids, acetyl

CoA, mevalonic acid and intermediates of
shikimic acid pathway
 Introduction to
Natural Products Chemistry

 Natural extracts were subjected to

separation into component compounds,
which were then purified and analyzed.

 In the late 1800's, synthetic methods

were being developed for some of these
natural compounds. 
Isolation Protocol

General
isolation
strategy of
natural
products:
Steps in the Isolation Process

 Dry the ground plant material

 Extract the dried and ground plant material with a
suitable solvent.
 Concentrate the extract.
 Separate and purify each component.
 Since the concentrate contains an enormous variety of
compounds, early isolations involved selective
crystallization of the most dominant component in the
mixture. 
Steps in the Isolation Process

 Since the concentrate contains an enormous variety of

compounds, early isolations involved selective
crystallization of the most dominant component in the
mixture. 

 Liquid natural products were distilled.  Natural organic

acids were isolated by aqueous basic extraction and
natural organic bases (alkaloids) were isolated by
aqueous acidic extraction.
 Purification

Column Chromatography
Thin Layer Chromatography
Gas Chromatographpy
High Pressure Liquid Chromatography
Ion Exchange Chromatography
Size Exclusion Chromatography
 Isolation Techniques

 Modern chromatographic methods have been

greatly developed to isolate and purify a large
number of different compounds in very small
quantities:  column chromatography, GC, TLC,
HPLC, paper, electrophoresis, ion exchange,
etc.
 Natural products are usually given names that
are derived from the species name of the plant
or animal, or from the biological action, or
property, of the compound.
 Early Techniques

 In the late 1800's, natural products were

identified and analyzed by mp, bp, [a]
(optical rotation), hoping to find
correlations between data and structure. 
 This initiative was not successful in
predicting structure, but useful data on
natural products were obtained.
Modern Isolation and
Characterization Techniques
And by other methods:  
 ORD (optical rotatory dispersion)
 CD (circular dichroism)
 acidity and basicity measurements (pK)
 advanced synthetic and biosynthetic technology
 X-ray crystallography
 Structure Elucidation

Ultraviolet spectroscopy
Infrared spectroscopy
Mass spectrometry
1H-Nuclear magnetic spectroscopy

13C-Nuclear magnetic spectroscopy

X-ray crystallography
Classical Structural Elucidations

 Determination of functional groups

 Determination of the carbon skeleton and the

location of the functional groups

 Degradation to smaller fragments

(A-B-C → A   +   B   +   C)

 Elemental analysis
Classical Structural Elucidations

 Reactivity (leading to new reactions)

 Stereochemistry

 Synthesis of the smaller fragments (A, B, C)

and the entire molecule (A-B-C)

 Classification of the compound into a

biogenetic family of compounds
Modern Structural Elucidation

 1930s UV (UltraViolet) light

(cf. Woodward's Rules, 1941)
 1940s IR (Infrared) spectroscopy (note: 
Penicillin structure problem in WW II)
 1950s NMR (Nuclear Magnetic Resonance)
spectroscopy
 1960s MS (Mass Spectrometry)
 ESR (electron spin resonance) spectroscopy
 
Introduction to Natural Products
Chemistry
 Modern methods reduces the necessity of
chemical degradation methods, so much less
material is required.
Why synthesize natural products?
 Structure determination
 Challenge
 Develop new synthetic methods
 Practical and commercial interests
Primary and Secondary Metabolism

Primary Metabolism
- metabolic pathways by which organisms
synthesize and utilize essential chemical
species; and the polymers derived from them
Secondary Metabolism
- metabolic pathways of organisms that
produce compounds which usually have no
apparent utility (natural products)
1. Shikimic Acid Pathway
2. Polyketide Pathway Biosynthesis
3. Mevalonic Acid Pathway Secondary Metabolites
Simple building blocks serve as the basis for each major
pathway of secondary metabolism:

(1) Shikimate Aromatics (ring - C3 chain)

(2) Amino acids Alkaloids, Penicillins

(N-containing)

(3) Mevalonate Terpenes, Steroids

(4) Acetate Polyketides

(aromatics, macrocycles)
www.lclark.edu/~seavey/plant%20cell72-1.jpg [14 june 2008]
 Vacuole

 Holding sites for metabolic by-products

 Contains small molecules, unlike the other
organelles (proteins, carbohydrates, etc.)
 Membrane bound sac used for storage
 Plays a role in intracellular digestion and
the release of waste products
 In plants, vacuoles play a huge role in
turgor pressure.
 BioAssays

 Cytotoxicity Test (Bhrine shrimp Assay)

 Oral Glucose Tolerance Test (OGTT)
 Micronucleus Test by Schmidt
 Ames Test
 Rec Assay
 Anti-Microbial Assay
 Anti-Oxidant Assay
 Acetic Acid Induced Writhing Test
 ADME TOX

ADME Tox is an area of drug

development for assessing the
potential safety concerns for new
compound entities (NCEs).

ADME tox studies evaluate how

a drug and/or its metabolites are
absorbed, distributed, metabolized,
and excreted from the body.

Drug metabolism issues is one of

the primary reasons why drug
candidates fail in clinical trials
 Cell-Based Assays for Cancer

ADME Tox Assays

 In vitro dissolution assay
 Intestinal absorption assays
 Metabolic stability and clearance
 Metabolic profiling
 Drug-drug interactions
 Assays for organ toxicity
 Integrated discrete multiple organ co-culture
technology (IdMOC)
 Enzyme-Based Assays
 For diabetes
amylase, alpha glucosidase, aldose reductase
 For inflammation
cyclooxygenase, lipoxygenase
 For hypertension
angiotensin-converting enzyme
 For uricosuria
xanthine oxidase
 For neurodegenerative disorders
cholinesterases
 For obesity
lipase